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41.
Elena Percivalle Fuliang Chu Durga Nattamai Megan Harline Seung‐Tae Lee Laura Bover Heather Y. Lin Veerabhadran Baladandayuthapani David Delgado Amber Luong R. Eric Davis Larry W. Kwak Yong‐Jun Liu Sattva S. Neelapu 《International journal of cancer. Journal international du cancer》2014,135(12):2834-2846
Immunotherapeutic strategies are promising approaches for the treatment of follicular lymphoma (FL). However, their efficacy may be limited by immunosuppressive elements in the immune system and tumor microenvironment. Therefore, strategies to reverse the effects of the immunosuppressive elements are needed. We observed that regulatory T cells (Tregs) were increased in the peripheral blood at diagnosis and persisted in high numbers after induction of clinical remission with a cyclophosphamide and doxorubicin‐containing chemotherapy regimen in FL patients. High levels of peripheral blood Tregs prior to therapy were associated with decreased progression‐free survival in FL patients treated with either chemotherapy or combination immunotherapy that targeted CD20 and PD‐1 with monoclonal antibodies rituximab and pidilizumab, respectively. Intratumoral and peripheral blood Tregs potently suppressed autologous antitumor effector T cells in FL. However, the effects of FL Tregs could be reversed by triggering Toll‐like receptors (TLR) with TLR ligands Pam3CSK4 (TLR 1/2), flagellin (TLR 5), and CpG‐B (TLR 9), and/or OX40. The TLR ligands synergized with each other as well as OX40 signaling to inhibit Tregs. Furthermore, they restored the function of FL tumor‐specific effector T cells. Our results suggest that a state of tolerance exists in FL patients at diagnosis and after induction of clinical remission, and agents that activate TLRs 1/2, 5, and 9, and OX40 may serve as adjuvants to enhance the efficacy of antitumor immunotherapeutic strategies and preventive vaccines against infectious diseases in these patients. 相似文献
42.
Alison K. Yoder Jillian R. Gunther Sarah A. Milgrom Dragan Mirkovic Loretta Nastoupil Sattva Neelapu Michelle Fanale Nathan Fowler Jason Westin Hun Ju Lee M.Alma Rodriguez Swaminathan P. Iyer Luis Fayad Yago L. Nieto Chitra Hosing Sairah Ahmed L.Jeffrey Medeiros Joseph D. Khoury Chelsea C. Pinnix 《Clinical Lymphoma, Myeloma & Leukemia》2019,19(1):e51-e61
Introduction
We report successful treatment of mesenteric diffuse large B-cell lymphoma (DLBCL) using localized involved site radiation therapy (ISRT), intensity modulated radiation therapy (IMRT), and daily computed tomography (CT)-image guidance.Patients and Methods
Patients with mesenteric DLBCL treated with RT between 2011 and 2017 were reviewed. Clinical and treatment characteristics were analyzed for an association with local control, progression-free survival (PFS), and overall survival.Results
Twenty-three patients were eligible. At diagnosis, the median age was 52 years (range, 38-76 years), and 57% (n = 13) had stage I/II DLBCL. All patients received frontline chemotherapy (ChT) (R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone], n = 19; dose-adjusted R-EPOCH [rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin], n = 4) with median 6 cycles. Prior to RT, salvage ChT for refractory DLBCL was given to 43% (n = 10) and autologous stem cell transplantation was administered in 13% (n = 3). At the time of RT, positron emission tomography-CT revealed 5-point scale of 1 to 3 (48%; n = 11), 4 (9%; n = 2), and 5 (44%; n = 10). All patients received IMRT, daily CT imaging, and ISRT. The median RT dose was 40 Gy (range, 16.2-49.4 Gy). Relapse or progression occurred in 22% (n = 5). At a median follow-up of 37 months, the 3-year local control, PFS, and overall survival rates were 80%, 75%, and 96%, respectively. Among patients treated with RT after complete metabolic response to frontline ChT (n = 8), the 3-year PFS was 100%, compared with 61% for patients with a history of chemorefractory DLBCL (n = 15; P = .055). Four of the 5 relapses occurred in patients with 5-point scale of 5 prior to RT (P = .127).Conclusion
Mesenteric involvement of DLBCL can be successfully targeted with localized ISRT fields using IMRT and daily CT-image guidance. 相似文献43.
44.
Younes A Oki Y Bociek RG Kuruvilla J Fanale M Neelapu S Copeland A Buglio D Galal A Besterman J Li Z Drouin M Patterson T Ward MR Paulus JK Ji Y Medeiros LJ Martell RE 《The lancet oncology》2011,(13):1222-1228
Background
The prognosis of patients with relapsed Hodgkin's lymphoma, especially those who relapse after stem-cell transplantation, is poor, and the development of new agents for this patient population is an unmet medical need. We tested the safety and efficacy of mocetinostat, an oral isotype-selective histone deacetylase inhibitor, in patients with relapsed classical Hodgkin's lymphoma.Methods
Patients with relapsed or refractory classical Hodgkin's lymphoma aged 18 years or older were treated with mocetinostat administered orally three times per week, in 28-day cycles. Two doses were assessed (85 mg and 110 mg). Patients were treated until disease progression or prohibitive toxicity. The primary outcome was disease control rate, defined as complete response, partial response, or stable disease (for at least six cycles), analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00358982.Findings
51 patients were enrolled. Initially, 23 patients were enrolled in the 110 mg cohort. Subsequently, because toxicity-related dose reductions were necessary in the 110 mg cohort, we treated 28 additional patients with a dose of 85 mg. On the basis of intent-to-treat analysis, the disease control rate was 35% (eight of 23 patients) in the 110 mg group and 25% (seven of 28) in the 85 mg group. 12 patients (24%) discontinued treatment because of adverse events, nine (32%) in the 85 mg cohort and three (13%) in the 110 mg cohort. The most frequent treatment-related grade 3 and 4 adverse events were neutropenia (four patients [17%] in the 110 mg group, three [11%] in the 85 mg group); fatigue (five patients [22%] in the 110 mg group, three [11%] in the 85 mg group); and pneumonia (four patients [17%] in the 110 mg group, two [7%] in the 85 mg group). Four patients, all in the 110 mg cohort, died during the study, of which two might have been related to treatment.Interpretation
Mocetinostat, 85 mg three times per week, has promising single-agent clinical activity with manageable toxicity in patients with relapsed classical Hodgkin's lymphoma.Funding
MethylGene Inc, Montreal, Canada; Celgene Corporation, Summit, NJ, USA; Tufts Medical Center, Boston, MA, USA. 相似文献45.
Preleukaemic clonal haemopoiesis and risk of therapy-related myeloid neoplasms: a case-control study
Koichi Takahashi Feng Wang Hagop Kantarjian Denaha Doss Kanhav Khanna Erika Thompson Li Zhao Keyur Patel Sattva Neelapu Curtis Gumbs Carlos Bueso-Ramos Courtney D DiNardo Simona Colla Farhad Ravandi Jianhua Zhang Xuelin Huang Xifeng Wu Felipe Samaniego P Andrew Futreal 《The lancet oncology》2017,18(1):100-111
46.
47.
Park HJ Qin H Cha SC Sharma R Chung Y Schluns KS Neelapu SS Overwijk WW Hwu P Kwak LW 《Vaccine》2011,29(18):3476-3482
Our laboratory previously described the strategy of fusing chemokine receptor ligands to antigens in order to generate immunogenic DNA vaccines. In the present study, we produced mouse β-2 defensin (mBD2) fusion proteins using both ovalbumin (OVA) and gp100 as model antigens. Superior cross-presentation by dendritic cells (DC) was observed for mBD2 fused antigens over unfused antigens in vitro. In vivo, we observed significant increases in the expansion of adoptively transferred antigen-specific MHC class I, but not class II-restricted T cells after immunization with mBD2 fused antigen over antigen alone. This enhanced expansion of class I restricted T cells was Toll-like receptor 4 (TLR4) dependent, but CC chemokine receptor 6 (CCR6) independent. Superior tumor resistance was observed for mBD2-fusion protein vaccines, compared to unfused antigen, in both B16-OVA and B16 tumor models. These data suggest that production of mBD2 fusion proteins is feasible and that the vaccines facilitate in vivo expansion of adoptively transferred T cells through a TLR4-dependent mechanism. 相似文献
48.
Cha SC Kwak LW Ruffini PA Qin H Neelapu S Biragyn A 《Journal of immunological methods》2006,312(1-2):79-93
Active immunization of follicular lymphoma patients with idiotypic vaccines elicits antigen-specific antibody responses, T-cell responses, and antitumor effects. We hypothesized that these vaccinated patients could generate tumor-specific immune responses, not only against idiotype, but also against other tumor-associated antigens (TAA) by a mechanism of epitope spreading. To identify potential antigens, a phage surface expressed cDNA library derived from primary tumor cells was screened with sera from idiotype-vaccinated patients. Consistent with our hypothesis, we identified two immunogenic peptides (FL-aa-7 and 18), unrelated to idiotype, which were recognized by postvaccine sera but not by prevaccine or normal human sera. These peptide sequences derived from the 5'-untranslated regions of the human GTPase, IMAP family member 7 gene (FL-aa-7) and an alternative reading frame of U1-snRNP 70 (FL-aa-18), respectively, suggesting that epitope spreading had occurred. 相似文献
49.
Idiotypic vaccination for B-cell malignancies as a model for therapeutic cancer vaccines: from prototype protein to second generation vaccines 总被引:11,自引:0,他引:11
BACKGROUND AND OBJECTIVES: Cancer vaccines are aimed at inducing tumor-specific immunity by immunizing patients with tumor cells or their antigenic components, known as tumor-associated antigens (TAA). Antigens which are either mutated or selectively or abundantly expressed in malignant, but not in normal, cells are considered as TAA. Each patient's B-cell malignancy is usually derived from a single expanded B-cell clone, which expresses an immunoglobulin (Ig) with a unique idiotype (Id, variable regions of Ig). Therefore, Id can be regarded as a TAA and a potential target in clinical vaccination approaches. Although use of tumor-derived Id as an immunogen to elicit antitumor immunity against B-cell malignancies is an attractive idea, the broader use of idiotypic vaccines has been hampered by the fact that autologous Id is not only a weakly immunogenic, self antigen, but is also patient-specific so that the vaccine must be individually prepared for each patient. In this review we will first summarize the latest data from the clinical tests of experimental idiotypic vaccines and discuss issues relevant to the clinical application of cancer vaccines in general; we will then critically review new trends and achievements in the development of the second generation vaccine formulations. EVIDENCE AND INFORMATION SOURCES: The authors of the present review are currently working in the field of B-cell tumor immunotherapy and have contributed original papers to peer-reviewed journals. The material analyzed in the present review includes articles and abstracts published in journals covered by the Science Citation Index and Medline. STATE OF ART: The results from a number of experimental models and clinical trials have demonstrated that vaccination with tumor-derived Id can induce immune responses directed against the tumor. Idiotypic vaccines can be divided into two types, although both are at the experimental stage: traditional and second generation, based on the methods of production and vaccine delivery. Second generation vaccines utilizing genetically engineered protein and DNA formulations have, for the first time, opened up the possibility of streamlining production of simpler and effective custom-made idiotypic vaccines. The use of various adjuvants and exogenous carriers is being replaced by more potent genetic carriers which target Id and various co-stimulatory molecules to professional antigen presenting cells (APC), particularly dendritic cells (DC). PERSPECTIVES: Id is the only widely accepted tumor marker and is a promising therapeutic target for immunotherapy of B-cell malignancies. It has been unequivocally established that Id vaccination of patients with follicular lymphoma administered when patients have minimal residual disease, has antitumor effect and potential to improve the clinical outcome. Consequently, the applicability of Id vaccines for other B-cell malignancies such as chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma needs to be tested. Idiotypic vaccines should be tailored to target preferentially various subsets of immune cells, such as DCs, which would up take and properly process and present Id, activating both arms of the immune system, humoral and cellular. Moreover, the vaccine should induce the production of a milieu of inflammatory cytokines and lymphokines at the delivery site to elicit a T helper type 1 (Th1) immune response. Components of the inflammatory response can be used to target DCs in vivo, activating the so-called danger signal for circumventing the poor immunogenicity of self-tumor antigens. For example, chemotactic factors of innate immunity are able to deliver Id to APC and render this otherwise non-immunogenic antigen immunogenic. The strategies developed for Id vaccines can be used as a general strategy for eliciting T-cell immunity to other weakly immunogenic, clinically relevant self-tumor antigens. 相似文献
50.